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Understanding the Functions and Relationships of the Glymphatic System and Meningeal Lymphatics

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Understanding the Functions and Relationships of the Glymphatic System and Meningeal Lymphatics Understanding the functions and relationships of the glymphatic system and meningeal lymphatics Antoine Louveau, … , Maiken Nedergaard, Jonathan Kipnis J Clin Invest. 2017;127(9):3210-3219. https://doi.org/10.1172/JCI90603. Review Series Recent discoveries of the glymphatic system and of meningeal lymphatic vessels have generated a lot of excitement, along with some degree of skepticism. Here, we summarize the state of the field and point out the gaps of knowledge that should be filled through further research. We discuss the glymphatic system as a system that allows CNS perfusion by the cerebrospinal fluid (CSF) and interstitial fluid (ISF). We also describe the recently characterized meningeal lymphatic vessels and their role in drainage of the brain ISF, CSF, CNS-derived molecules, and immune cells from the CNS and meninges to the peripheral (CNS-draining) lymph nodes. We speculate on the relationship between the two systems and their malfunction that may underlie some neurological diseases. Although much remains to be investigated, these new discoveries have changed our understanding of mechanisms underlying CNS immune privilege and CNS drainage. Future studies should explore the communications between the glymphatic system and meningeal lymphatics in CNS disorders and develop new therapeutic modalities targeting these systems. Find the latest version: https://jci.me/90603/pdf REVIEW SERIES: GLIA AND NEURODEGENERATION The Journal of Clinical Investigation Series Editors: Marco Colonna and David Holtzmann Understanding the functions and relationships of the glymphatic system and meningeal lymphatics Antoine Louveau,1 Benjamin A. Plog,2 Salli Antila,3 Kari Alitalo,3 Maiken Nedergaard,2,4 and Jonathan Kipnis1 1Center for Brain Immunology and Glia, Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, Virginia, USA. 2Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York, USA. 3Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland. 4Center of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Recent discoveries of the glymphatic system and of meningeal lymphatic vessels have generated a lot of excitement, along with some degree of skepticism. Here, we summarize the state of the field and point out the gaps of knowledge that should be filled through further research. We discuss the glymphatic system as a system that allows CNS perfusion by the cerebrospinal fluid (CSF) and interstitial fluid (ISF). We also describe the recently characterized meningeal lymphatic vessels and their role in drainage of the brain ISF, CSF, CNS-derived molecules, and immune cells from the CNS and meninges to the peripheral (CNS-draining) lymph nodes. We speculate on the relationship between the two systems and their malfunction that may underlie some neurological diseases. Although much remains to be investigated, these new discoveries have changed our understanding of mechanisms underlying CNS immune privilege and CNS drainage. Future studies should explore the communications between the glymphatic system and meningeal lymphatics in CNS disorders and develop new therapeutic modalities targeting these systems. Perivascular pathways: pseudolymphatic vessels bral blood vessels (10, 11). Molecules of vastly different molecular of the brain? weights, such as albumin (69 kDa) and polyethylene glycols (900 In peripheral organs, colloids are extravasated across a fenestrated Da and 4 kDa), all cleared from brain with nearly identical half- capillary bed, and these proteins, as well as excess tissue fluid, are times of disappearance, leading to the conclusion that the efflux of returned to the circulating blood through a dense network of lym- ISF and its constituent solutes was by bulk fluid flow and not dif- phatic vessels (1, 2). In the CNS, the blood-brain barrier prevents fusion (12). Similarly, HRP injected into the CSF of cats was found unregulated protein and fluid entry into brain (3, 4); however, solu- to use these same perivascular conduits to rapidly enter the brain, ble waste products are still released into the brain’s interstitial spac- penetrating to the level of capillary basement membranes within es as a consequence of its high metabolic rate. The CNS is the only 4 to 10 minutes of injection (13, 14). Consequently, a model was organ system of the body lacking classically defined lymphatic ves- advanced in which the brain’s perivascular spaces were assigned sels and tissues, and as a result has developed unique adaptations a pseudolymphatic function, acting as ducts to remove metabolic for waste clearance and fluid balance (5). Choroid plexus epithelial waste products and deliver fresh CSF to the interstitium. cells actively secrete cerebrospinal fluid (CSF) within the cerebral ventricles (4, 6–8), ultimately draining into the subarachnoid space The glymphatic system: anatomy and function (SAS) surrounding the brain, which has long been considered to in health and disease act as a sink for interstitial waste (6, 9). How metabolites produced Observations that ISF and CSF were moving in opposite direc- and released deep within the brain’s extracellular spaces ultimately tions within this exchange pathway led to the hypothesis that clear to the subarachnoid CSF compartment remains a persistent there are discrete subsets of perivascular spaces specialized question (7–9). Early studies of the anatomy of brain waste clear- for either ISF efflux or CSF influx. In an attempt to identify the ance used tracer molecules to identify pathways of interstitial fluid inflow and clearance arms of this system, Iliff and colleagues (ISF) and solute drainage from the parenchyma. Injection of Blue (15) injected fluorescent tracers into the CSF and striatum of Dextran 2000 or horseradish peroxidase (HRP) directly into the Tie2-GFP:NG2-DsRed double reporter mice to visualize all cere- caudate nucleus of rats showed that these interstitial solutes did not bral blood vessels based on GFP-expressing endothelial cells move through the parenchyma isotropically, but rather drained via (ECs) and DsRed-expressing perivascular cells (15). Here they preferential pathways, specifically the perivascular spaces of cere- observed that CSF-based tracer entered the brain specifically within the perivascular spaces of double-positive vessels, indica- tive of cerebral-penetrating arteries, whereas ISF tracer drained Authorship note: A. Louveau, B.A. Plog, and S. Antila contributed equally to this work. from brain exclusively alongside single-positive large caliber K. Alitalo, M. Nedergaard, and J. Kipnis contributed equally to this work and are veins, such as the internal cerebral and caudal rhinal veins (15). co–senior authors. Additionally, perivascular aquaporin-4 (AQP4) channels, dense- Conflict of interest: The authors have declared that no conflict of interest exists. Reference information: J Clin Invest. 2017;127(9):3210–3219. ly expressed in astrocyte end-foot processes (16), were found to https://doi.org/10.1172/JCI90603. play an important role in facilitating flow through this pathway. 3210 jci.org Volume 127 Number 9 September 2017 The Journal of Clinical Investigation REVIEW SERIES: GLIA AND NEURODEGENERATION Figure 1. Circulation of CSF, ISF, and brain solute through the glymphat- ic pathway. (A) CSF within the subarachnoid and cisternal spaces flows into brain specifically via periarterial spaces and then exchanges with ISF facilitated by aquaporin-4 (AQP4) water channels that are positioned within perivascular astrocyte end-foot processes. The bulk movement of CSF into brain drives the convective flow of ISF and interstitial solute through the extracellular space to ultimately collect within perivenous spaces. (B) Perivenous fluid and solute then drain from brain predominantly alongside large-caliber ventral veins. Once within the subarachnoid CSF, solutes such as amyloid-β can exit the cranium via arachnoid granulations or meningeal lymphatic vessels or along cranial and spinal nerves; however, a proportion is also capable of recirculating into brain via periarterial spaces. Periarterial sol- ute may seed and accumulate within the basement membranes of smooth muscle cells, precipitating conditions such as cerebral amyloid angiopathy. knockout, CSF volume reduction, or alteration of posture all led to increased brain and reduced cervical lymph node lactate lev- els (21), even in the clearance-promoting anesthetized state (20). The importance of glymphatic clearance of interstitial solute is perhaps best demonstrated by the fact that its failure contributes to the pathophysiology of various CNS diseases. In the aged brain and in a murine transgenic model of Alzheimer’s disease, glym- phatic CSF influx is reduced and the clearance of Aβ is profoundly impaired (22, 23). Interestingly, pretreating young wild-type mice with Aβ suppressed glymphatic influx, suggesting that not only is Aβ aggregation a consequence of a breakdown of flow within this pathway, but it may also be an independent cause of glymphatic dysfunction (23). Further, glymphatic impairment is a prominent feature of cerebrovascular disease, including both subarachnoid hemorrhage and multiple microinfarction (24, 25). Following traumatic brain injury, reduced clearance of cortical interstitial solute was associated with motor and cognitive neurological defi- cits (26). While CSF-ISF exchange within
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